NLRP12

{{Short description|Protein-coding gene in the species Homo sapiens}}

Nucleotide-binding oligomerization domain-like receptor (NLR) pyrin domain (PYD)-containing protein 12 (NLRP12; also known as NACHT, LRR and PYD domains-containing protein 12 or NALP12) is a protein that in humans is encoded by the NLRP12 gene.{{cite journal |vauthors=Tschopp J, Martinon F, Burns K |date=Feb 2003 |title=NALPs: a novel protein family involved in inflammation |url=https://www.nature.com/articles/nrm1019 |journal=Nat Rev Mol Cell Biol |volume=4 |issue=2 |pages=95–104 |doi=10.1038/nrm1019 |pmid=12563287 |s2cid=31417018}}{{cite journal | vauthors = Wang L, Manji GA, Grenier JM, Al-Garawi A, Merriam S, Lora JM, Geddes BJ, Briskin M, DiStefano PS, Bertin J | title = PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing | journal = J Biol Chem | volume = 277 | issue = 33 | pages = 29874–80 |date=Aug 2002 | pmid = 12019269 | doi = 10.1074/jbc.M203915200 | doi-access = free }}{{cite web | title = Entrez Gene: NLRP12 NLR family, pyrin domain containing 12| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=91662}}

NLRP structure

NLRPs, or NALPs, are cytoplasmic innate immune sensors that form a subfamily within the larger CATERPILLER protein family. Most short NLRP proteins, including NLRP12, have an N-terminal pyrin (MEFV; MIM 608107) domain (PYD), followed by a NACHT domain, a NACHT-associated domain (NAD), and a C-terminal leucine-rich repeat (LRR) region. The long NALP, NALP1 (MIM 606636), also has a C-terminal extension containing a function to find domain (FIIND) and a caspase recruitment domain (CARD).

Some NLRPs, including NLRP12, are implicated in the activation of proinflammatory caspases (e.g., CASP1; MIM 147678) via their involvement in multiprotein complexes called inflammasomes in context-dependent manners{{Cite journal |last1=Tschopp |first1=Jürg |last2=Martinon |first2=Fabio |last3=Burns |first3=Kimberly |year=2003 |title=NALPs: a novel protein family involved in inflammation. |journal=Nat Rev Mol Cell Biol |volume=4 |issue=3 |pages=95–104|doi=10.1038/nrm1019 |pmid=12563287 }} [supplied by OMIM].

NLRP12 function and pathology

NLRP12 is an innate immune cytosolic sensor and signaling molecule linked to several infections and inflammatory disorders.{{Cite journal |title=NLRP12 in innate immunity and inflammation |journal=Molecular Aspects of Medicine|date=2020 |pmid=32838963 |volume=76 |doi=10.1016/j.mam.2020.100887 |pmc=9375713 | vauthors = Tuladhar S, Kanneganti T }} It can form multimeric protein cell death complexes known as inflammasomes and PANoptosomes in response to specific stimuli.{{Cite journal |title=The NLRP12 Inflammasome Recognizes Yersinia pestis |journal=Immunity |date=2012 |doi=10.1016/j.immuni.2012.07.006 |language=en |volume=37 |pages=96–107 | vauthors = Vladimer GI, Weng D, Paquette SW, Vanaja SK, Rathinam VA, Aune MH, Conlon JE, Burbage JJ, Proulx MK, Liu Q, Reed G, Mecsas JC, Iwakura Y, Bertin J, Goguen JD, Fitzgerald KA, Lien E |issue=1 |pmid=22840842 |pmc=3753114 }}{{Cite journal |last1=Ataide |first1=Marco A. |last2=Andrade |first2=Warrison A. |last3=Zamboni |first3=Dario S. |last4=Wang |first4=Donghai |last5=Souza |first5=Maria do Carmo |last6=Franklin |first6=Bernardo S. |last7=Elian |first7=Samir |last8=Martins |first8=Flaviano S. |last9=Pereira |first9=Dhelio |last10=Reed |first10=George |last11=Fitzgerald |first11=Katherine A. |last12=Golenbock |first12=Douglas T. |last13=Gazzinelli |first13=Ricardo T. |date=2014-01-16 |editor-last=Sibley |editor-first=L. David |title=Malaria-Induced NLRP12/NLRP3-Dependent Caspase-1 Activation Mediates Inflammation and Hypersensitivity to Bacterial Superinfection |journal=PLOS Pathogens |language=en |volume=10 |issue=1 |pages=e1003885 |doi=10.1371/journal.ppat.1003885 |issn=1553-7374 |pmc=3894209 |pmid=24453977 |doi-access=free}}{{Cite journal |title=NLRP12-PANoptosome activates PANoptosis and pathology in response to heme and PAMPs |journal=Cell|date=2023 |pmid=37267949 |author7=Malireddi RKS |volume=186 |issue=13 |pages=2783–2801.e20 |doi=10.1016/j.cell.2023.05.005 |pmc=10330523 | vauthors = Sundaram B, Pandian N, Mall R, Wang Y, Sarkar R, Kim HJ }}{{Cite web |title=St. Jude finds NLRP12 as a new drug target for infection, inflammation and hemolytic diseases |url=https://www.stjude.org/media-resources/news-releases/2023-medicine-science-news/st-jude-finds-nlrp12-as-a-new-drug-target.html |access-date=2024-02-20 |website=www.stjude.org |language=en}} NLRP12 has been reported as both a positive and negative regulator of immune signaling in context-dependent manners.{{Cite journal |last1=Pinheiro |first1=Anderson S. |last2=Eibl |first2=Clarissa |last3=Ekman-Vural |first3=Zeynep |last4=Schwarzenbacher |first4=Robert |last5=Peti |first5=Wolfgang |date=2011-11-04 |title=The NLRP12 Pyrin Domain: Structure, Dynamics, and Functional Insights |journal=Journal of Molecular Biology |volume=413 |issue=4 |pages=790–803 |doi=10.1016/j.jmb.2011.09.024 |issn=0022-2836 |pmc=3202057 |pmid=21978668}}{{Cite journal |last1=Tuncer |first1=Sinem |last2=Fiorillo |first2=Maria Teresa |last3=Sorrentino |first3=Rosa |date=2014-09-23 |title=The multifaceted nature of NLRP12 |url=https://academic.oup.com/jleukbio/article/96/6/991/6935861 |journal=Journal of Leukocyte Biology |language=en |volume=96 |issue=6 |pages=991–1000 |doi=10.1189/jlb.3RU0514-265RR |pmid=25249449 |s2cid=30257891 |issn=0741-5400}}{{Cite journal |title=PYPAF7, a Novel PYRIN-containing Apaf1-like Protein That Regulates Activation of NF-κB and Caspase-1-dependent Cytokine Processing |journal=Journal of Biological Chemistry|date=2002 |pmid=12019269 |volume=277 |issue=33 |pages=29874–29880 |doi=10.1074/jbc.M203915200 |doi-access=free | vauthors = Wang L, Manji GA, Grenier JM, Al-Garawi A, Merriam S, Lora JM, Geddes BJ, Briskin M, Distefano PS, Bertin J }} Infection with certain pathogens, such as Yersinia pestis or Plasmodium chabaudi, activates the NLRP12 inflammasome to release the inflammatory cytokines IL-1β and IL-18, which may help protect against severe infection.

However, NLRP12 acts as a negative regulator of the NF-kB and MAPK signaling pathways following infection with Salmonella enterica serovar Typhimurium, vesicular stomatitis virus, Klebsiella pneumoniae, or Mycobacterium tuberculosis, and in certain malignancies.{{Cite journal |title=NLRP12 Suppresses Colon Inflammation and Tumorigenesis through the Negative Regulation of Noncanonical NF-κB Signaling |journal=Immunity|date=2012 |pmid=22503542 |volume=36 |issue=5 |pages=742–754 |doi=10.1016/j.immuni.2012.03.012 |pmc=3658309 | vauthors = Allen IC, Wilson JE, Schneider M, Lich JD, Roberts RA, Arthur JC, Woodford RM, Davis BK, Uronis JM, Herfarth HH, Jobin C, Rogers AB, Ting JP }} NLRP12 also inhibits signaling in T cells, which is linked to reduced atypical neuroinflammation and atopic dermatitis in mouse models.{{Cite journal |title=The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4 Production in T Cells |journal=Immunity|date=2015 |pmid=25888258 |volume=42 |issue=4 |pages=654–664 |doi=10.1016/j.immuni.2015.03.006 |pmc=4412374 | vauthors = Lukens JR, Gurung P, Shaw PJ, Barr MJ, Zaki MH, Brown SA, Vogel P, Chi H, Kanneganti TD }} NLRP12 has also been identified as an innate immune sensor that triggers inflammatory cell death, PANoptosis. PANoptosis is a prominent innate immune, inflammatory, and lytic cell death pathway initiated by innate immune sensors and driven by caspases and receptor-interacting protein kinases (RIPKs) through PANoptosomes. PANoptosomes are multi-protein complexes assembled by germline-encoded pattern-recognition receptor(s) (PRRs) (innate immune sensor(s)) in response to pathogens, including bacterial, viral, and fungal infections, as well as pathogen-associated molecular patterns, damage-associated molecular patterns, cytokines, and homeostatic changes during infections, inflammatory conditions, and cancer.{{Cite web |date=2021-10-19 |title=Promising preclinical cancer therapy harnesses a newly discovered cell death pathway |url=https://www.stjude.org/media-resources/news-releases/2021-medicine-science-news/promising-preclinical-cancer-therapy-harnesses-a-newly-discovered-cell-death-pathway.html |access-date=2024-08-13 |website=www.stjude.org}}{{Cite web |date=2022-05-22 |title=ZBP1 links interferon treatment and dangerous inflammatory cell death during COVID-19 |url=https://www.stjude.org/media-resources/news-releases/2022-medicine-science-news/zbp1-links-interferon-treatment-and-cell-death-during-covid-19.html |access-date=2024-08-13 |website=www.stjude.org}}{{Cite web |date=2021-09-01 |title=The PANoptosome: a new frontier in innate immune responses |url=https://www.stjude.org/media-resources/news-releases/2021-medicine-science-news/the-panoptosome-a-new-frontier-in-innate-immune-responses.html |website=www.stjude.org}}{{Cite web |date=2020-11-18 |title=In the lab, St. Jude scientists identify possible COVID-19 treatment |url=https://www.stjude.org/media-resources/news-releases/2020-medicine-science-news/in-the-lab-st-jude-scientists-identify-possible-covid-19-treatment.html |access-date=2024-08-13 |website=www.stjude.org}}{{Cite web |date=2020-04-15 |title=Discovering the secrets of the enigmatic caspase-6 |url=https://www.stjude.org/media-resources/news-releases/2020-medicine-science-news/discovering-the-secrets-of-the-enigmatic-caspase-6.html |access-date=2024-08-13 |website=www.stjude.org}}{{Cite web |date=2019-12-23 |title=Breaking the dogma: Key cell death regulator has more than one way to get the job done |url=https://www.stjude.org/media-resources/news-releases/2019-medicine-science-news/key-cell-death-regulator-gets-job-done.html |access-date=2024-08-13}}{{Cite journal |last1=Kuriakose |first1=Teneema |last2=Si Ming |first2=Man |last3=R.K. 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Subbarao |last2=Rajendra |first2=Karki |last3=Sundaram |first3=Balamurugan |last4=Kancharana |first4=Balabhaskararao |last5=Lee |first5=SangJoon |last6=Samir |first6=Parimal |last7=Kanneganti |first7=Thirumala-Devi |title=Inflammatory cell death, PANoptosis, mediated by cytokines in diverse cancer lineages inhibits tumor growth |journal=ImmunoHorizons |date=2021 |volume=5 |issue=7 |pages=568–580 |doi=10.4049/immunohorizons.2100059 |pmc=8522052 |pmid=34290111}}{{Cite journal |last1=Karki |first1=Rajendra |last2=Sharma |first2=Bhesh Raj |last3=Tuladhar |first3=Shraddha |last4=Williams |first4=Evan Peter |last5=Zalduondo |first5=Lillian |last6=Samir |first6=Parimal |last7=Zheng |first7=Min |last8=Sundaram |first8=Balamurugan |last9=Banoth |first9=Balaji |last10=Malireddi |first10=R. K. 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Through its activation of PANoptosis, NLRP12 has been implicated in pathology when heme is combined with specific components of cellular injury or infection. This combination enables NLRP12 to assemble the NLRP12-PANoptosome and trigger cell death via caspase-8 and RIPK3. NLRP12 can also form a PANoptosome complex with other NLRs, including NLRC5 and NLRP3, in response to NAD⁺ depletion, driving PANoptosis.{{Cite web |last=St. Jude Children's Research Hospital |date=2024-06-14 |title=St. Jude scientists solve decades long mystery of NLRC5 sensor function in cell death and disease |url=https://www.stjude.org/media-resources/news-releases/2024-medicine-science-news/scientists-solve-decades-long-mystery-of-nlrc5-sensor-function-in-cell-death.html |access-date=2024-08-13 |website=www.stjude.org.}}{{Cite journal |last1=Sundaram |first1=Balamurugan |last2=Pandian |first2=Nagakannan |last3=Kim |first3=Hee Jin |last4=Abdelaal |first4=Hadia M. |last5=Mall |first5=Raghvendra |last6=Indari |first6=Omkar |last7=Sarkar |first7=Roman |last8=Tweedell |first8=Rebecca E. |last9=Alonzo |first9=Emily Q. |last10=Klein |first10=Jonathon |last11=Pruett-Miller |first11=Shondra M. |last12=Vogel |first12=Peter |last13=Kanneganti |first13=Thirumala-Devi |title=NLRC5 senses NAD+ depletion, forming a PANoptosome and driving PANoptosis and inflammation |journal=Cell |date=2024 |volume=187 |issue=15 |pages=4061–4077 |doi=10.1016/j.cell.2024.05.034 |pmc=11283362 |pmid=38878777}} NLRP12 expression is also elevated in patients with hemolytic diseases such as sickle cell disease and malaria, as well as infections such as SARS-CoV-2, influenza, and bacterial pneumonia.{{Cite journal |last1=Parnell |first1=Grant P |last2=McLean |first2=Anthony S |last3=Booth |first3=David R |last4=Armstrong |first4=Nicola J |last5=Nalos |first5=Marek |last6=Huang |first6=Stephen J |last7=Manak |first7=Jan |last8=Tang |first8=Wilson |last9=Tam |first9=Oi-Yan |last10=Chan |first10=Stanley |last11=Tang |first11=Benjamin M |date=2012 |title=A distinct influenza infection signature in the blood transcriptome of patients with severe community-acquired pneumonia |journal=Critical Care |language=en |volume=16 |issue=4 |pages=R157 |doi=10.1186/cc11477 |doi-access=free |issn=1364-8535 |pmc=3580747 |pmid=22898401}}{{Cite journal |title=NLRP12-PANoptosome in haemolytic, infectious and inflammatory diseases |journal=Clinical and Translational Medicine|date=2023 |pmid=37700491 |volume=13 |issue=9 |pages=e1409 |doi=10.1002/ctm2.1409 |pmc=10497829 | vauthors = Tweedell RE, Kanneganti T }} Deletion of Nlrp12 protects against pathology in animal models of hemolytic disease.

NLRP12

NLRP structure

NLRP12 function and pathology

References

Further reading